3-hydroxymethyl-4hydroxy-phenyl- derivatives for the treatment of respiratory diseases

ABSTRACT

The present invention relates to the use of the compounds of general formula 1 
     
       
         
         
             
             
         
       
     
     wherein the groups R 1 , X and Y may have the meanings given in the claims and in the specification, for preparing a pharmaceutical composition for the treatment of COPD (chronic obstructive pulmonary disease), as well as new compounds of general formula 1 and processes for preparing them.

The present invention relates to compounds of general formula 1

wherein the groups R¹, X and Y may have the meanings given in the claimsand in the specification, processes for preparing them and their use aspharmaceutical compositions, particularly for the treatment ofinflammatory and obstructive respiratory complaints.

BACKGROUND TO THE INVENTION

Betamimetics (β-adrenergic substances) are known from the prior art. Inthis respect reference is made for example to the disclosure of U.S.Pat. No. 4,647,563, which proposes betamimetics for the treatment of awide range of diseases.

For the drug treatment of diseases it is often desirable to preparemedicaments with a longer duration of activity. As a rule, this ensuresthat the concentration of the active substance in the body needed toachieve the therapeutic effect is guaranteed for a longer period withoutthe need to re-administer the drug at frequent intervals. Moreover,giving an active substance at longer time intervals contributes to thewellbeing of the patient to a high degree. It is particularly desirableto prepare a pharmaceutical composition which can be usedtherapeutically by administration once a day (single dose). The use of adrug once a day has the advantage that the patient can become accustomedrelatively quickly to regularly taking the drug at certain times of theday.

The aim of the present invention is therefore to provide betamimeticswhich are characterised by a longer duration of activity and can thus beused to prepare pharmaceutical compositions with a longer duration ofactivity. A particular aim of the invention is to prepare betamimeticswhich, by virtue of their long-lasting effect, can be used to prepare adrug for administration once a day. A further objective of the inventionis to prepare new betamimetics which, by virtue of their long-lastingeffect, can be used to prepare a drug for administration once a day forthe treatment of inflammatory or obstructive respiratory complaints.

In addition to the above objectives, the present invention also sets outto provide betamimetics which are not only exceptionally potent but arealso characterised by a high degree of selectivity with respect to theβ₂-adreno-receptor.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly it has been found that the above-mentioned objectives areachieved by compounds of general formula 1.

Accordingly, the present invention relates to compounds of generalformula 1

wherein

-   X denotes nitrogen, oxygen or CR²;-   Y denotes nitrogen, oxygen or CR³;-   R¹ denotes hydrogen, C₁-C₄-alkyl, halogen, OH or —O—C₁-C₄-alkyl;-   R² denotes hydrogen, C₁-C₄-alkyl, halogen, OH or —O—C₁-C₄-alkyl, or    -   phenyl, which may optionally be mono-, di- or trisubstituted by        one or more groups selected from among C₁-C₄-alkyl, halogen, OH        or —O—C₁-C₄-alkyl;-   R³ denotes hydrogen, C₁-C₄-alkyl, halogen, OH or —O—C₁-C₄-alkyl; or-   R² and R³ together denote a bridging group —CH═CH—CH═CH, wherein    one, two or three hydrogen atoms are substituted by a group selected    from among C₁-C₄-alkyl, OH, halogen and —O—C₁-C₄-alkyl,    with the proviso that R¹ cannot be hydrogen if the groups R² and R³    denote hydrogen, optionally in the form of the individual optical    isomers, mixtures of the individual enantiomers or racemates, in the    form of the free bases or of the corresponding acid addition salts    with pharmacologically harmless acids.

Preferred compounds of general formula 1 are those wherein

-   X denotes nitrogen or CR²;-   Y denotes nitrogen or CR³;-   R¹ denotes hydrogen, methyl, ethyl, fluorine, chlorine, bromine, OH    or methoxy, preferably hydrogen or methyl;-   R² denotes methyl, fluorine, chlorine, bromine, OH or methoxy or    -   phenyl, which may optionally be mono- or disubstituted by one or        more groups selected from among methyl, fluorine, chlorine,        bromine, OH or methoxy;-   R³ denotes hydrogen, methyl, fluorine, chlorine, bromine, OH or    methoxy, optionally in the form of the individual optical isomers,    mixtures of the individual enantiomers or racemates, in the form of    the free bases or of the corresponding acid addition salts with    pharmacologically harmless acids.

Also preferred are the above compounds of general formula 1, wherein

-   X denotes CR²;-   Y denotes nitrogen;-   R¹ denotes hydrogen, methyl or ethyl;-   R² denotes phenyl, which may optionally be mono- or disubstituted by    one or more groups selected from among methyl, fluorine, chlorine,    bromine, OH or methoxy;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or of the corresponding acid addition salts with    pharmacologically harmless acids.

Also preferred are compounds of general formula 1, wherein

-   X denotes CR²;-   Y denotes nitrogen;-   R¹ denotes hydrogen, methyl or ethyl;-   R² denotes phenyl, which may be mono- or disubstituted by methyl,    fluorine or methoxy;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or of the corresponding acid addition salts with    pharmacologically harmless acids.

Particularly preferred are compounds of general formula 1, wherein

-   X denotes nitrogen or CR²;-   Y denotes nitrogen or CR³;-   R¹ denotes hydrogen or methyl, preferably hydrogen;-   R² denotes methyl, OH or methoxy, or    -   phenyl, which may optionally be monosubstituted by a group        selected from among methyl, OH or methoxy, preferably methoxy;-   R³ denotes hydrogen, methyl, OH or methoxy,    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or of the corresponding acid addition salts with    pharmacologically harmless acids.

Also particularly preferred are compounds of general formula 1, wherein

-   X denotes nitrogen or CR²;-   Y denotes nitrogen or CR³, preferably CR³;-   R¹ denotes hydrogen;-   R² denotes phenyl, which may optionally be substituted by OH or    methoxy, preferably methoxy;-   R³ denotes hydrogen;    optionally in the form of the individual optical isomers, mixtures    of the individual enantiomers or racemates, in the form of the free    bases or of the corresponding acid addition salts with    pharmacologically harmless acids.

By acid addition salts with pharmacologically acceptable acids aremeant, for example, the salts selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferablythe hydrochloride, hydrobromide, hydrosulphate, hydrophosphate,hydrofumarate and hydromethanesulphonate.

The compounds of general formula 1 may optionally be used in the form ofthe individual optical isomers, mixtures of the individual enantiomersor racemates. If the compounds are used in enantiomerically pure form,the R-enantiomers are preferably used.

Unless otherwise stated, the alkyl groups are straight-chained orbranched alkyl groups having 1 to 4 carbon atoms. The following arementioned by way of example: methyl, ethyl, propyl or butyl. In somecases the abbreviations Me, Et, Prop or Bu are used to denote the groupsmethyl, ethyl, propyl or butyl. Unless otherwise stated, the definitionspropyl and butyl include all the possible isomeric forms of the groupsin question. Thus, for example, propyl includes n-propyl and iso-propyl,butyl includes iso-butyl, sec.butyl and tert.-butyl, etc.

Unless otherwise stated, the term alkyloxy groups (or —O-alkyl groups)denotes branched and unbranched alkyl groups having 1 to 4 carbon atomswhich are linked via an oxygen atom. Examples of these include:methyloxy, ethyloxy, propyloxy or butyloxy. The abbreviations MeO-,EtO-, PropO- or BuO- are used in some cases to denote the groupsmethyloxy, ethyloxy, propyloxy or butyloxy. Unless otherwise stated, thedefinitions propyloxy and butyloxy include all possible isomeric formsof the groups in question. Thus, for example, propyloxy includesn-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy,sec.butyloxy and tert.-butyloxy, etc. In some cases, within the scope ofthe present invention, the term alkoxy is used instead of the termalkyloxy. Accordingly, the terms methoxy, ethoxy, propoxy or butoxy mayalso be used to denote the groups methyloxy, ethyloxy, propyloxy orbutyloxy.

Halogen within the scope of the present invention denotes fluorine,chlorine, bromine or iodine. Unless stated otherwise, fluorine, chlorineand bromine are the preferred halogens.

The compounds according to the invention may be prepared analogously tomethods already known from the prior art. Suitable methods ofpreparation are known for example from U.S. Pat. No. 4,647,563, to theentire contents of which reference is made at this point.

The examples of synthesis described below serve to illustrate newcompounds according to the invention in more detail. However, they areintended only as examples of procedures to illustrate the inventionwithout restricting it to the subject matter described in anexemplifying capacity hereinafter.

Example 14-[2-(1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylamino)-1-hydroxy-ethyl]-2-hydroxymethyl-phenol

a) methyl2-benzyloxy-5-[2-(1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylimino)-acetyl]-benzoate16 g of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 6g of 1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylamine are heated to 70° C.for one hour in 100 mL ethanol. Then half the solvent is distilled offand the mixture remaining is cooled. The product that crystallises outis suction filtered and washed with ethanol and diethyl ether.

-   Yield: 15.3 g (91%); m.p.=170-172° C.    b) methyl    2-benzyloxy-5-[2-(1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylamino)-acetyl]-benzoate    15.3 g of the Schiff's base are placed in 150 mL ethanol, cooled to    10° C. and combined batchwise with 1.1 g of sodium borohydride. The    mixture is stirred for 2 hours at ambient temperature and then    combined with 10 mL acetone. After another 30 minutes stirring a    further 50 mL water are added, the mixture is acidified with glacial    acetic acid and the ethanol is distilled off. The residue is    combined with 100 mL water, washed twice with ethyl acetate, made    alkaline with ammonia and extracted once with 150 mL ethyl acetate.    The organic phase is dried with sodium sulphate and evaporated down.    Yield: 14 g of yellow oil (91%).    c)    1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-(1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylamino)-ethanol    5 g of calcium chloride are dissolved in 50 mL ethanol. Then 10 g of    methyl    2-benzyloxy-5-[2-(1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylamino)-acetyl]-benzoate    in 100 mL tetrahydrofuran are added and the mixture is cooled to    5° C. It is combined batchwise with 3.5 g of sodium borohydride and    stirred overnight while heating to ambient temperature. 15 mL    acetone are added to the reaction mixture and it is stirred for 30    minutes. Glacial acetic acid is added, the solvents are distilled    off, 100 mL water are added to the residue and it is adjusted to pH    2 with conc. hydrochloric acid. It is washed once with ethyl    acetate, then made basic with ammonia, diluted with 100 mL water and    extracted twice with in each case 200 mL ethyl acetate. After the    organic phase has been dried it is evaporated down and the residue    is dissolved in acetonitrile. The mixture is acidified with glacial    acetic acid and seed crystals are added. The product precipitated is    suction filtered and recrystallised from acetonitrile. Yield: 6.5 g    (43%, acetate); m.p.=139-141° C.    d)    4-[2-(1,1-dimethyl-3-,[1,2,4]triazol-4-yl-propylamino)-1-hydroxy-ethyl]-2-hydroxymethyl-phenol    5 g of    1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-(1,1-dimethyl-3-[1,2,4]triazol-4-yl-propylamino)-ethanol    acetate are hydrogenated with 0.5 g of palladium on charcoal (5%) in    100 mL methanol. After the theoretically calculated amount of    hydrogen has been taken up the catalyst is filtered off and the    filtrate is evaporated down. The residue is dissolved in 10 mL    ethanol and seeded. Then the product that crystallises out is    suction filtered and washed. Yield: 3.2 g (74%, acetate);    m.p.=125-127° C.

Example 24-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-2-hydroxymethyl-phenol

a) methyl2-benzyloxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-benzoate8.5 g of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and4.9 g of3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylaminein 100 mL ethanol are stirred for three hours at 60° C., cooled to 10°C., combined batchwise with 0.8 g of sodium borohydride and stirred fora further three hours at ambient temperature. Then 10 mL acetone areadded and the mixture is stirred for one hour. It is then poured ontoice and acidified with glacial acetic acid. The ethanol is distilledoff, the aqueous phase remaining is made alkaline with sodium hydroxideand extracted with ethyl acetate. The organic phases are dried withsodium sulphate and evaporated down. The residue is combined with 80 mLethanol, acidified with 3.2 g of oxalic acid, dissolved in ethanol, andseeded. The product that crystallises out is suction filtered andwashed. Yield: 8 g (69%, oxalate); m.p.=210-213° C.b)1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-{3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1dimethyl-propylamino}-ethanolAnalogously to the method used for Example 1c, 10 g of methyl2-benzyloxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-benzoate,in 100 mL tetrahydrofuran, are reacted with a solution of 4.6 g ofcalcium chloride in 50 mL ethanol, as well as 3.1 g of sodiumborohydride. After a reaction period of 1.5 days another 4.6 g ofcalcium chloride, dissolved in 50 mL ethanol, and 3.1 g of sodiumborohydride are added. The reaction mixture is then worked up asdescribed. Purification by column chromatography(CHCl₃/MeOH/NH₃=90/10/0.5) yields the product in the form of acolourless oil.

-   Yield: 5 g (51%); m.p. (ethyl acetate)=139-141° C.    c)    4-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-2-hydroxymethyl-phenol    5 g of    1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-{3-[3-(4-methoxy-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-    1,1-dimethyl-propylamino }-ethanol dissolved in 100 mL methanol are    hydrogenated under normal pressure with 1 g of palladium on charcoal    (5%) as catalyst. Then the catalyst is separated off and the    filtrate is evaporated down. The residue is dissolved in 15 mL    acetonitrile, acidified with 0.5 mL glacial acetic acid and seeded.    The solid precipitated is filtered off and washed with acetonitrile    and diethyl ether. Yield: 3.8 g (78%, acetate); m.p.=110-116° C.

Example 34-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-2-hydroxymethyl-phenol

a) methyl2-benzyloxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-benzoate14 g of methyl benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 7.7g of 3-[3-(4-methoxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamine arereacted with 1.1 g of sodium borohydride analogously to the method usedfor Example 2a and worked up. After the reaction mixture has been pouredonto ice and combined with glacial acetic acid, the mixture is acidifiedwith conc. hydrochloric acid. The dihydrochloride precipitated isfiltered off, washed with acetone and diethyl ether and recrystallisedfrom 75% ethanol.

-   Yield: 15 g (82%, dihydrochloride); 230-232° C.    b)    1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-{3-[3-(4-methoxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamino    }-ethanol    13 g of methyl    2-benzyloxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-benzoate    in 100 mL tetrahydrofuran are reacted with a solution of 6.5 g of    calcium chloride in 65 mL ethanol and 4.5 g of sodium borohydride    analogously to the method used for Example 1c. After a reaction time    of 12 hours, 3 g of calcium chloride, dissolved in 30 mL ethanol,    and 2 g of sodium borohydride are added and stirring is continued    for a further 12 hours. Then the mixture is worked up as described,    except that extraction is carried out using chloroform rather than    ethyl acetate. During the evaporation of this organic phase a solid    is precipitated out. The solid is suction filtered, stirred with    ethyl acetate and recrystallised from acetonitrile. Yield: 79.5 g    (77%); m.p.=108-111° C.    c)    4-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-2-hydroxymethyl-phenol    9.4 g of    1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-{3-[3-(4-methoxy-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamino}-ethanol    are dissolved in 50 mL tetrahydrofuran and 80 mL methanol and    hydrogenated in the presence of 1 g of palladium on charcoal (5%).    After the theoretically calculated amount of hydrogen has been taken    up the catalyst is suction filtered and the filtrate is freed from    solvent. The residue is dissolved in 20 mL tetrahydrofuran,    acidified with 1.1 mL glacial acetic acid and combined with 1 mL    water. After the addition of seed crystals the precipitated product    is filtered off and washed.-   Yield: 7.4 g (84%, acetate), m.p.=136-140° C.

Example 44-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-2-hydroxymethyl-phenol

a) methyl2-benzyloxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-benzoateThe reaction and working up of 7.65 g of2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate methyl and 4.7 g of3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamineare carried out analogously to the method described for Example 2a. Thecrude product is then converted into an oxalate in the usual way.

-   Yield: 8.5 g (85%, oxalate).    b)    1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethanol    7.3 g of methyl    2-benzyloxy-5-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-benzoate    are placed in 100 mL tetrahydrofuran and reduced with a total of 6.8    g of calcium chloride dissolved in ethanol and 4.6 g of sodium    borohydride as described for Example 1c. The product is obtained    after purification by column chromatography    (CHCl₃/MeOH/NH₃=90/10/0.5) and subsequent recrystallisation from    acetonitrile.-   Yield: 4 g (58%); m.p.=120-123° C.    c)    4-(1-hydroxy-2-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethyl)-2-hydroxymethyl-phenol    3.8 g of    1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-ethanol    are hydrogenated with 0.6 g of palladium on charcoal (5%) as    catalyst in 75 mL methanol and 75 mL tetrahydrofuran. Then the    catalyst is suction filtered and the filtrate is evaporated down.    The residue is dissolved in 15 mL 15%m acetonitrile, acidified with    formic acid and combined with a crystallisation aid. The    precipitated product is separated off and washed. Yield: 2.8 g (81%,    formate); m.p.=142-145° C.

Example 54-[2-(1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamino)-1-hydroxy-ethyl]-2-hydroxymethyl-phenol

a) methyl2-benzyloxy-5-[2-[1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamino]-1-hydroxy-ethyl]-benzoate9.5 g of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and3.1 g of 1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamine are reacted andworked up analogously to the method described for Example 2a. The crudeproduct is dissolved in 100 mL 95% ethanol and combined with anethanolic solution of 1.8 g of oxalic acid. After the addition of acrystallisation aid the precipitated product is separated off andwashed. Yield: 8 g (64%, bisoxalate), m.p.=220-222° C.b)1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-(1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamino)-ethanol7.6 g of methyl2-benzyloxy-5-[2-[1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamino]-1-hydroxy-ethyl]-benzoateare reduced in an ethanolic calcium chloride solution with sodiumborohydride as described for Example 1c. The product is obtained as acolourless oil after purification by column chromatography(CHCl₃/MeOH/NH₃=90/10/0.5). Yield: 6 g (84%).c)4-[2-(1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamino)-1-hydroxy-ethyl]-2-hydroxymethyl-phenolThe debenzylation of 6 g of1-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-(1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamino)-ethanolis carried out hydrogenolytically with 1 g of palladium on charcoal (5%)in 100 mL methanol. After the catalyst has been removed by suctionfiltering and the filtrate has been evaporated down the residue isdissolved in 20 mL 90% ethanol, combined with sulphuric acid and seeded.The precipitated product is filtered off and washed. Yield: 3 g (55%,hemisulphate); m.p.=177-180° C.

The compounds according to the invention of Examples 6-9 were alsoobtained using the methods of synthesis described below.

Synthesis of the precursors for Examples 6-9:

Precursor 1)1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl]-propylamine

P-1-a) 4-methyl-benzoic acid-(1-imino-ethyl)-hydrazide1.65 g (72 mmol) of sodium are dissolved in 80 mL ethanol. 8.89 g (72mmol) of ethylacetimidate hydrochloride in 160 mL ethanol are added atambient temperature and the precipitated sodium chloride is filteredoff. The filtrate is combined with 6.00 g (40 mmol) 4-methyl-benzoicacid hydrazide and stirred overnight. The reaction mixture is evaporateddown and cooled. The precipitated solid is filtered off and washed withcold ethanol and diethyl ether (5.7 g of white solid). A further 1.2 gof solid are obtained from the filtrate after the removal of the solventby distillation and recrystallisation from ethanol. Yield: 6.93 g (91%);mass spectroscopy [M+H]⁺=192.P-1-b) 5-methyl-3-p-tolyl-[1,2,4]triazole7.58 g (40 mmol) 4-methyl-benzoic acid-(1-imino-ethyl)-hydrazide areheated to 180° C. for 30 minutes with stirring. After cooling the solidis dissolved in chloroform. The precipitate formed on cooling is suctionfiltered and recrystallised from chloroform.

-   Yield: 4.82 g (70%); mass spectroscopy [M+H]⁺=174.    P-1-c)    tert.butyl[1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl)-propyl]-carbamate    1.35 g (34 mmol, 60%) sodium hydride are added to a solution of 4.87    g (28 mmol) of 5-methyl-3-p-tolyl-[1,2,4]triazole in 40 mL DMPU at    0° C. The reaction mixture is heated to ambient temperature and then    stirred for one hour. 9.35 g (42 mmol) of tert.butyl    (3-chloro-1,1-dimethyl-propyl)-carbamate and 1.87 g (5 mmol) of    tetrabutylammonium iodide are added and the mixture is stirred    overnight at ambient temperature and then for 2 hours at 80° C. It    is combined with water and ethyl acetate, the aqueous phase is    separated off and extracted with ethyl acetate. The combined organic    phases are washed with water and sodium chloride solution, dried    with sodium sulphate and evaporated down. The residue is purified by    column chromatography (silica gel; petroleum ether/ethyl    acetate=1.1). Oil.-   Yield: 2.97 g (30%); mass spectroscopy [M+H]⁺=359.    P-1-d)    1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl]-propylamine    A total of 11 mL trifluoroacetic acid are added dropwise to a    solution of 2.97 g (8.3 mmol) of tert.butyl    [1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl)-propyl]-carbamate    in 80 mL dichloromethane and the mixture is stirred overnight at    ambient temperature. The solvent is distilled off and the residue is    combined with diethyl ether and stirred. The precipitated solid is    filtered off and washed. Yield: 2.11 g (68%, trifluoroacetate); mass    spectroscopy [M+H]⁺=259.    Precursor 2)    3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine

P-2-a) 4-fluoro-benzoic acid-(1-imino-ethyl)-hydrazidePrepared from 7.2 g (58 mmol) of ethylacetimidate hydrochloride and 5.00g (32 mmol) of 4-fluoro-benzoic acid hydrazide analogously to the methoddescribed under P-1-a).

-   Yield: 5.78 g (91%); mass spectroscopy [M+H]⁺=196.    P-2-b) 3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazole    The compound is prepared analogously to the method described in    P-1-b) from 5.77 g (30 mmol) of 4-fluoro-benzoic    acid-(1-imino-ethyl)-hydrazide.-   Yield: 4.11 g (78%); mass spectroscopy [M+H]⁺=178.    P-2-c) tert.butyl    {3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4triazol-1-yl]-1,1-dimethyl-propyl}-carbamate    5.88 g (33 mmol) of 3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazole are    dissolved in 40 mL DMPU and reacted with 11.04 g (50 mmol) of    tert.butyl (3-chloro-1,1-dimethyl-propyl)-carbamate, 1.59 g (40    mmol, 60%) of sodium hydride and 2.21 g (6 mmol) of    tetrabutylammonium iodide in the manner described in P-1-c).-   Yield: 4.22 g (35%); mass spectroscopy [M+H]⁺=363.    P-2-d)    3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine    Obtained by reacting 4.22 g (11.6 mmol) of tert.butyl    {3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propyl    }-carbamate in 100 mL dichloromethane and 15 mL trifluoroacetic    acid. White solid.-   Yield: 4.43 g (trifluoroacetate); mass spectroscopy [M+H]⁺=263.    Precursor 3)    3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine

P-3-a) 3,5-difluoro-benzoic acid-(1-imino-ethyl)-hydrazideObtained from 4.91 g (40 mmol) of ethylacetimidate hydrochloride and3.80 g (22 mmol) of 3,5 difluoro-benzoic acid hydrazide analogously tothe method described in P-1-a).

-   Yield: 4.49 g (95%); mass spectroscopy [M+H]⁺=214.    P-3-b) 3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazole    Prepared from 4.61 g (22 mmol) of 3,5-difluoro-benzoic    acid-(1-imino-ethyl)-hydrazide.-   Yield: 3.81 g (91%); mass spectroscopy [M+H]⁺=196.    P-3-c) tert.butyl    {3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propyl}-carbamate    3.74 g (19 mmol) of 3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazole    in 25 mL DMPU are reacted with 0.92 g (23 mmol, 60%) of sodium    hydride, 6.37 g (29 mmol) of tert.butyl    (3-chloro-1,1-dimethyl-propyl)-carbamate and 1.27 g (3.5 mmol) of    tetrabutylammonium iodide analogously to P-1-c). Oil.-   Yield: 2.62 g (36%); mass spectroscopy [M+H]⁺=381.    P-3-d)    3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine    2.62 g (6.9 mmol) of tert.butyl    {3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propyl}-carbamate    in 65 mL dichloromethane are reacted with 9 mL trifluoroacetic acid    in the manner described in P-1-d). White solid.-   Yield: 2.11 g (trifluoroacetate); mass spectroscopy [M+H]⁺=281.    Precursor 4)    3-[5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine

P-4-a) 4-methoxy-benzoic acid-(1-imino-propyl)-hydrazidePrepared from 4.90 g (45 mmol) of propioamidine hydrochloride and 5.00 g(30 mmol) of 4-methoxy-benzoic acid hydrazide analogously to the methoddescribed in P-1-a). After the ethanol has been distilled off 10.0 g ofcrude product are obtained which are reacted without any furtherpurification.P-4-b) 5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazole9.99 g (60%, approx. 28 mmol) of 4-methoxy-benzoicacid-(1-imino-propyl)-hydrazide are heated to 150° C. for two hours.After cooling the melt is purified by chromatography on a silica gelcolumn (petroleum ether/ethyl acetate=3/7). Light yellow solid. Yield:4.56 g (75% over two steps); mass spectroscopy [M+H]⁺=204.P-4-c) tert.butyl{3-[5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propyl-carbamate4.30 g (21.2 mmol) of 5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazole aredissolved in 30 mL DMPU and cooled to 0° C. Then 1.02 g (24 mmol, 60%)of sodium hydride are added batchwise under a protective gas atmosphereand the reaction mixture is slowly heated to ambient temperature andthen stirred one hour. 6.10 g (27.5 mmol) of tert.butyl(3-chloro-1,1-dimethyl-propyl)-carbamate and 1.41 g (3.8 mmol) oftetrabutylammonium iodide are added. The mixture is stirred overnightand then the reaction is ended by the addition of water and ethylacetate. The aqueous phase is separated off and extracted with ethylacetate. The combined organic phases are washed with sodium chloridesolution, dried with sodium sulphate and evaporated down. The oilremaining is purified by chromatography on a silica gel column(petroleum ether/ethyl acetate=3:7).

-   Yield: 6.82 g (83%); mass spectroscopy [M+H]⁺=389.    P-4-d)    3-[5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine    A total of 20 mL trifluoroacetic acid are added dropwise to a    solution of 6.81 g (17.5 mmol) of tert.butyl {    3-[5-ethyl-3-(4-methoxy-phenyl)-    [1,2,4]triazol-1-yl]-1,1-dimethyl-propyl-carbamate in 150 mL    dichloromethane. After three hours stirring at ambient temperature    the solution is evaporated down and the oil remaining is combined    with diethyl ether. The white solid precipitated is filtered off,    washed with diethyl ether and dried.-   Yield: 7.86 g (trifluoroacetate); mass spectroscopy [M+H]⁺=289.

General Working Method A for Synthesising Examples 6 to 9:

1 mmol of glyoxal aldehyde or acetal and 1 mmol of amine are stirred for15 minutes in 5 mL tetrahydrofuran at 60° C. The mixture is cooled to 0°C. and under an argon atmosphere 2 mL of a 2 molar solution of lithiumborohydride in tetrahydrofuran are added dropwise thereto. The mixtureis stirred for 15 min at 0° C., then heated to ambient temperature and afurther 2 mL of the lithium borohydride solution are added. After 5hours at 50° C. 10 mL dichloromethane and 3 mL water are added, themixture is stirred for 30 minutes at ambient temperature and thenfiltered through diatomite, eluting with dichloromethane and methanol.The eluate is freed from solvent and if necessary the residue ispurified by chromatography. The benzylether thus obtained is dissolvedin methanol and hydrogenated with palladium on charcoal (10%) ascatalyst at normal pressure and ambient temperature. Then the catalystis separated off and the crude product is purified by chromatography(reverse phase, acetonitrile/water gradient) or recrystallised fromacetonitrile.

Example 64-{2-[1,1-dimethyl-3-(5-methyl-3-p-tolyl-[1,2,4]triazol-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxymethyl-phenol

The compound is prepared analogously to the general working method Afrom 241 mg (0.7 mmol) of methyl2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 181 mg (0.7 mmol)of 1,1-dimethyl-3-(5-methyl-3-p-tolyl- [1,2,4]triazol-1-yl)-propylamine.

-   Yield: 13 mg (4%); mass spectroscopy [M+H]⁺=425.

Example 74-(2-{3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol

The compound is obtained according to general working method A from 121mg (0.35 mmol) of methyl2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 98 mg (0.35 mmol)of 3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine.

-   Yield: 9 mg (6%); mass spectroscopy [M+H]⁺=447.

Example 84-(2-{3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol

Prepared according to general working method A from 344 mg (1 mmol) ofmethyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 262 mg (1mmol) of3-[3-(4-fluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine.

-   Yield: 8 mg (2%); mass spectroscopy [M+H]⁺=429.

Example 94-(2-{3-[5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol

The compound is prepared analogously to the general working method Afrom 344 mg (1 mmol) of methyl2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 262 mg (1 mmol)of3-[5-ethyl-3-(4-methoxy-phenyl)-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine.The debenzylation is carried out with Raney nickel as catalyst at 3 barand ambient temperature in ethanol. During the final purification bychromatography 0.1% trifluoroacetic acid is added to the eluant(acetonitrile/water gradient).

-   Yield: 102 mg (18%, trifluoroacetate); mass spectroscopy [M+H]⁺=455.

As has been found, the compounds of general formula 1 are characterisedby their range of uses in the therapeutic field. Particular mentionshould be made of those applications for which the compounds of formula1 according to the invention may preferably be used on the basis oftheir pharmaceutical activity as betamimetics.

These include, for example, the treatment of inflammatory andobstructive respiratory complaints, preferably the treatment of asthmaor COPD (chronic obstructive pulmonary disease), the inhibition ofpremature labour in midwifery (tocolysis), the restoration of the sinusrhythm in the heart in cases of atrio-ventricular block as well as thecorrecting of bradycardiac heart rhythm disorders (antiarrhythmicagent), the treatment of circulatory shock (vasodilatation andincreasing the heart-time volume) as well as the treatment of itchingand skin inflammation.

In one aspect the present invention relates to the use of the compoundsof general formula 1 as pharmaceutical compositions. In another aspectthe present invention relates to the use of the compounds of generalformula 1 for preparing a pharmaceutical composition for the treatmentof diseases, wherein therapeutically effective doses of a betamimeticcan deliver a therapeutic benefit. It is particularly preferable to usecompounds of general formula 1 for preparing a pharmaceuticalcomposition for the treatment of inflammatory and obstructiverespiratory complaints, particularly preferably the treatment of asthmaor COPD, for inhibiting premature labour in midwifery (tocolysis), forrestoring the sinus rhythm in the heart in cases of atrio-ventricularblock, for correcting bradycardiac heart rhythm disorders, for treatingcirculatory shock (vasodilatation and increasing the heart-time volume)and for the treatment of itching and skin inflammation. It isparticularly preferred according to the invention to use compounds ofgeneral formula 1 for preparing a pharmaceutical composition for thetreatment of inflammatory and obstructive respiratory complaints,particularly preferably for the treatment of asthma or COPD. Also ofparticular importance is the use of compounds of general formula 1 asdescribed above for preparing a pharmaceutical composition for aonce-a-day treatment of inflammatory and obstructive respiratorycomplaints, particularly preferably for a once-a-day treatment of asthmaor COPD.

The compounds of general formula 1 may be used on their own or inconjunction with other active substances of formula 1 according to theinvention. The compounds of general formula 1 may optionally also beused in combination with other pharmacologically active substances.These may be, in particular, anticholinergics, possibly otherbetamimetics, antiallergics, PDE-IV inhibitors, PAF antagonists,leukotriene antagonists and steroids as well as combinations of activesubstances thereof.

Examples of anticholinergics which may be mentioned are ipratropiumbromide, oxitropium bromide and particularly tiotropium bromide. Drugcombinations which contain tiotropium bromide, optionally in the form ofone of its solvates or hydrates, as another active substance in additionto the compounds of formula 1 according to the invention areparticularly preferred according to the invention. Tiotropium bromide isparticularly preferably used in the form of its monohydrate,particularly in the form of its crystalline monohydrate. Thiscrystalline monohydrate is described in detail in WO 02/30928.

Within the scope of the present invention, the corticosteroids which mayoptionally be used in conjunction with the compounds of formula 1 may becompounds selected from among flunisolide, beclomethasone,triamcinolone, budesonide, fluticasone, mometasone, ciclesonide,rofleponide and dexamethasone. Preferably, within the scope of thepresent invention, the corticosteroids are selected from amongflunisolide, beclomethasone, triamcinolone, budesonide, fluticasone,mometasone, ciclesonide and dexamethasone, while in this instancebudesonide, fluticasone, mometasone and ciclesonide are important andbudesonide and fluticasone are particularly important. In some cases,within the scope of the present patent application, the term steroids isused on its own instead of the word corticosteroids. Any reference tosteroids within the scope of the present invention includes a referenceto salts or derivatives which may be formed from the steroids. Examplesof possible salts or derivatives include: sodium salts, sulphobenzoates,phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates. In some cases thecorticosteroids may also occur in the form of their hydrates.

Within the scope of the present invention, the term dopamine agonists,which may optionally be used in conjunction with the compounds offormula 1, denotes compounds selected from among bromocriptine,cabergolin, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol,roxindol, ropinirol, talipexol, tergurid and viozan. It is preferablewithin the scope of the present invention to use, as combinationpartners with the compound of formula 1, dopamine agonists selected fromamong pramipexol, talipexol and viozan, pramipexol being of particularimportance. Any reference to the abovementioned dopamine agonists alsoincludes, within the scope of the present invention, a reference to anypharmacologically acceptable acid addition salts and hydrates thereofwhich may exist. By the physiologically acceptable acid addition saltsthereof which may be formed by the above-mentioned dopamine agonists aremeant, for example, pharmaceutically acceptable salts selected fromamong the salts of hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

Examples of antiallergic agents which may be used according to theinvention as a combination with the compound of formula 1 includeepinastin, cetirizin, azelastin, fexofenadin, levocabastin, loratadine,mizolastin, ketotifen, emedastin, dimetinden, clemastine, bamipin,cexchloropheniramine, pheniramine, doxylamine, chlorophenoxamine,dimenhydrinate, diphenhydramine, promethazine, ebastin, desloratidineand meclizine. Preferred antiallergic agents which may be used withinthe scope of the present invention in combination with the compounds offormula 1 according to the invention are selected from among epinastin,cetirizin, azelastin, fexofenadin, levocabastin, loratadine, ebastin,desloratidine and mizolastin, epinastin and desloratidine beingparticularly preferred. Any reference to the above-mentionedantiallergic agents also includes, within the scope of the presentinvention, a reference to any pharmacologically acceptable acid additionsalts thereof which may exist.

Examples of PDE-IV inhibitors which may be used according to theinvention as a combination with the compound of formula 1 includecompounds selected from among enprofylline, roflumilast, ariflo,Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A andAWD-12-281. Preferred PDE-IV inhibitors are selected from amongenprofylline, roflumilast, ariflo and AWD-12-281, while AWD-12-281 isparticularly preferred as the combination partner with the compound offormula 1 according to the invention. Any reference to theabove-mentioned PDE-IV inhibitors also includes, within the scope of thepresent invention, a reference to any pharmacologically acceptable acidaddition salts thereof which may exist. By the physiologicallyacceptable acid addition salts which may be formed by the abovementionedPDE-IV inhibitors are meant, according to the invention,pharmaceutically acceptable salts selected from among the salts ofhydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid or maleic acid. According to theinvention, the salts selected from among the acetate, hydrochloride,hydrobromide, sulphate, phosphate and methanesulphonate are preferred inthis context.

Suitable preparations for administering the compounds of formula 1include for example tablets, capsules, suppositories, solutions,powders, etc. The content of the pharmaceutically active compound(s)should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-%of the composition as a whole. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions are prepared in the usual way, e.g. with the addition ofisotonic agents, preservatives such as p-hydroxybenzoates or stabiliserssuch as alkali metal salts of ethylenediaminetetraacetic acid,optionally using emulsifiers and/or dispersants, while if water is usedas diluent, for example, organic solvents may optionally be used assolubilisers or dissolving aids, and the solutions may be transferredinto injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules. Suitable suppositories may be made forexample by mixing with carriers provided for this purpose, such asneutral fats or polyethyleneglycol or the derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral use the tablets may obviously contain, in addition to thecarriers specified, additives such as sodium citrate, calcium carbonateand dicalcium phosphate together with various additional substances suchas starch, preferably potato starch, gelatine and the like. Lubricantssuch as magnesium stearate, sodium laurylsulphate and talc may also beused to produce the tablets. In the case of aqueous suspensions theactive substances may be combined with various flavour enhancers orcolourings in addition to the abovementioned excipients.

In the preferred use of the compounds of formula 1 for the treatment ofasthma or COPD according to the invention it is particularly preferredto use preparations or pharmaceutical formulations which are suitablefor inhalation. Inhalable preparations include inhalable powders,propellant-containing metered-dose aerosols or propellant-free inhalablesolutions Within the scope of the present invention, the termpropellant-free inhalable solutions also includes concentrates orsterile ready-to-use inhalable solutions. The formulations which may beused within the scope of the present invention are described in moredetail in the next part of the specification

The inhalable powders which may be used according to the invention maycontain 1 either on its own or in admixture with suitablephysiologically acceptable excipients.

If the active substances 1 are present in admixture with physiologicallyacceptable excipients, the following physiologically acceptableexcipients may be used to prepare these inhalable powders according tothe invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients. Preferably, mono- or disaccharides are used, while theuse of lactose or glucose is preferred, particularly, but notexclusively, in the form of their hydrates. For the purposes of theinvention, lactose is the particularly preferred excipient, whilelactose monohydrate is most particularly preferred.

Within the scope of the inhalable powders according to the invention theexcipients have a maximum average particle size of up to 250 μm,preferably between 10 and 150 μm, most preferably between 15 and 80 μm.In some cases it may seem appropriate to add finer excipient fractionswith an average particle size of 1 to 9 μm to the excipient mentionedabove. These finer excipients are also selected from the group ofpossible excipients listed hereinbefore. Finally, in order to preparethe inhalable powders according to the invention, micronised activesubstance 1, preferably with an average particle size of 0.5 to 10 μm,more preferably from 1 to 5 μm, is added to the excipient mixture.Processes for producing the inhalable powders according to the inventionby grinding and micronising and lastly mixing the ingredients togetherare known from the prior art.

The inhalable powders according to the invention may be administeredusing inhalers known from the prior art.

The inhalation aerosols containing propellant gas according to theinvention may contain the compounds 1 dissolved in the propellant gas orin dispersed form. The compounds 1 may be contained in separateformulations or in a common formulation, in which the compounds 1 areeither both dissolved, both dispersed or in each case only one componentis dissolved and the other is dispersed. The propellant gases which maybe used to prepare the inhalation aerosols are known from the prior art.Suitable propellant gases are selected from among hydrocarbons such asn-propane, n-butane or isobutane and halohydrocarbons such asfluorinated derivatives of methane, ethane, propane, butane,cyclopropane or cyclobutane. The above-mentioned propellant gases may beused on their own or mixed together. Particularly preferred propellantgases are halogenated alkane derivatives selected from TG134a and TG227and mixtures thereof.

The propellant-driven inhalation aerosols may also contain otheringredients such as co--solvents, stabilisers, surfactants,antioxidants, lubricants and pH adjusters. All these ingredients areknown in the art.

The propellant-driven inhalation aerosols according to the inventionmentioned above may be administered using inhalers known in the art(MDIs=metered dose inhalers).

Moreover, the active substances 1 according to the invention may beadministered in the form of propellant-free inhalable solutions andsuspensions. The solvent used may be an aqueous or alcoholic, preferablyan ethanolic solution. The solvent may be water on its own or a mixtureof water and ethanol. The relative proportion of ethanol compared withwater is not limited but the maximum is preferably up to 70 percent byvolume, more particularly up to 60 percent by volume and most preferablyup to 30 percent by volume. The remainder of the volume is made up ofwater. The solutions or suspensions containing 1 are adjusted to a pH of2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjustedusing acids selected from inorganic or organic acids. Examples ofparticularly suitable inorganic acids include hydrochloric acid,hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.Examples of particularly suitable organic acids include ascorbic acid,citric acid, malic acid, tartaric acid, maleic acid, succinic acid,fumaric acid, acetic acid, formic acid and/or propionic acid etc.Preferred inorganic acids are hydrochloric and sulphuric acids. It isalso possible to use the acids which have already formed an acidaddition salt with one of the active substances. Of the organic acids,ascorbic acid, fumaric acid and citric acid are preferred. If desired,mixtures of the above acids may be used, particularly in the case ofacids which have other properties in addition to their acidifyingqualities, e.g. as flavourings, antioxidants or complexing agents, suchas citric acid or ascorbic acid, for example. According to theinvention, it is particularly preferred to use hydrochloric acid toadjust the pH.

If desired, the addition of editic acid (EDTA) or one of the known saltsthereof, sodium edetate, as stabiliser or complexing agent may beomitted in these formulations. Other embodiments may contain thiscompound or these compounds. In a preferred embodiment the content basedon sodium edetate is less than 100 mg/100 ml, preferably less than50mg/100 ml, more preferably less than 20mg/100ml. Generally, inhalablesolutions in which the content of sodium edetate is from 0 to 10 mg/100ml are preferred.

Co-solvents and/or other excipients may be added to the propellant-freeinhalable solutions. Preferred co-solvents are those which containhydroxyl groups or other polar groups, e.g. alcohols—particularlyisopropyl alcohol, glycols—particularly propyleneglycol,polyethyleneglycol, polypropyleneglycol, glycolether, glycerol,polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Theterms excipients and additives in this context denote anypharmacologically acceptable substance which is not an active substancebut which can be formulated with the active substance or substances inthe physiologically suitable solvent in order to improve the qualitativeproperties of the active substance formulation. Preferably, thesesubstances have no pharmacological effect or, in connection with thedesired therapy, no appreciable or at least no undesirablepharmacological effect. The excipients and additives include, forexample, surfactants such as soya lecithin, oleic acid, sorbitan esters,such as polysorbates, polyvinylpyrrolidone, other stabilisers,complexing agents, antioxidants and/or preservatives which guarantee orprolong the shelf life of the finished pharmaceutical formulation,flavourings, vitamins and/or other additives known in the art. Theadditives also include pharmacologically acceptable salts such as sodiumchloride as isotonic agents.

The preferred excipients include antioxidants such as ascorbic acid, forexample, provided that it has not already been used to adjust the pH,vitamin A, vitamin E, tocopherols and similar vitamins and provitaminsoccurring in the human body.

Preservatives may be used to protect the formulation from contaminationwith pathogens. Suitable preservatives are those which are known in theart, particularly cetyl pyridinium chloride, benzalkonium chloride orbenzoic acid or benzoates such as sodium benzoate in the concentrationknown from the prior art. The preservatives mentioned above arepreferably present in concentrations of up to 50 mg/100 ml, morepreferably between 5 and 20 mg/100 ml.

Preferred formulations contain, in addition to the solvent water and theactive substance 1, only benzalkonium chloride and sodium edetate. Inanother preferred embodiment, no sodium edetate is present.

The dosage of the compounds according to the invention is naturallyhighly dependent on the method of administration and the complaint whichis being treated. When administered by inhalation the compounds offormula 1 are characterised by a high potency even at doses in the μgrange. The compounds of formula 1 may also be used effectively above theμg range. The dosage may then be in the gram range, for example.

In another aspect the present invention relates to the above-mentionedpharmaceutical formulations as such, which are characterised in thatthey contain a compound of formula 1, particularly preferably theabove-mentioned pharmaceutical formulations administered by inhalation.

The following examples of formulations illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance 1 100 mg lactose 140 mg cornstarch 240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg 500mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance 1 80 mg lactose 55 mg corn starch190 mg  microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mgsodium-carboxymethyl starch 23 mg magnesium stearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed inand the mixture is compressed to form tablets of a suitable size.

C) Ampoule solution active substance 1 50 mg sodium chloride 50 mg waterfor inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

D) Metering aerosol Active substance 1 0.005 Sorbitan trioleate 0.1Monofluorotrichloromethane and ad 100 T134a:TG227

The suspension is transferred into a conventional aerosol container witha metering valve. Preferably, 50 μl of suspension are delivered perspray. The active substance may also be metered in higher doses ifdesired (e.g. 0.02% by weight).

E) Solutions (in mg/100 ml) Active substance 1 333.3 mg Tiotropiumbromide 333.3 mg Benzalkonium chloride  10.0 mg EDTA  50.0 mg HCl (1n)ad pH 3.4

This solution may be prepared in the usual manner.

F) Powder for inhalation Active substance 1 6 μg Tiotropium bromidemonohydrate 6 μg Lactose monohydrate ad 25 mg

The powder for inhalation is produced in the usual way by mixing theindividual ingredients together.

1-9. (canceled)
 10. A method of treating a disease in which atherapeutically effective dose of a betamimetic can provide atherapeutic benefit, wherein the method comprises administering to apatient in need thereof an effective amount of a compound of formula 1:

wherein: X denotes nitrogen, oxygen or CR²; Y denotes nitrogen, oxygenor CR³; R¹ denotes hydrogen, C₁C₄-alkyl, halogen, OH or —O—C₁-C₄-alkyl;R² denotes hydrogen, C₁-C₄-alkyl, halogen, OH or —O—C₁-C₄-alkyl, orphenyl, which may optionally be mono-, di- or trisubstituted by one ormore groups selected from among C₁-C₄-alkyl, halogen, OH or—O—C₁-C₄-alkyl; and R³ denotes hydrogen, C₁-C₄-alkyl, halogen, OH or—O—C₁-C₄-alkyl; or R² and R³ together denote a bridging group—CH═CH—CH═CH, wherein one, two or three hydrogen atoms are substitutedby a group selected from among C₁-C₄-alkyl, OH, halogen and—O—C₁-C₄-alkyl; with the proviso that R² cannot be hydrogen if thegroups R¹ and R³ denote hydrogen; or optical isomers, mixtures ofenantiomers or racemates, and pharmacologically acceptable saltsthereof.